Reduced natural oscillatory frequency of DLPFC in early course SCZ: a TMS/EEG study Project Summary: Schizophrenia (SCZ) leads to persistent, often treatment resistant impairments in patients? cognitive functioning. To ameliorate these cognitive deficits, one approach is to identify biomarkers of the underlying neural circuit defects, especially early in the illness, which can then be utilized for targeted treatment interventions. The overarching goal of this proposal is to determine whether oscillatory deficits of the dorsolateral prefrontal cortex (DLPFC), assessed with transcranial magnetic stimulation (TMS), are an early neurophysiological biomarker of prefrontal circuit deficits and related cognitive impairments in SCZ. Neurophysiological biomarkers offer precise temporal measures of cortical circuits that mediate cognitive features of SCZ. A ?perturb and measure? approach using TMS with EEG (TMS/EEG) enables the assessment of cortical oscillations independent of conscious effort, thus facilitating a biologically-driven approach to precision/personalized medicine in psychiatric populations. In previous work, we found that patients with chronic schizophrenia (Ch-SCZ) had reduced TMS- assessed frontal oscillations, including lower gamma-range power and coherence and that these reductions were most prominent in DLPFC. TMS/EEG also allows the characterization of the main oscillatory activity, or natural frequency, of cortical circuits. We recently found a slower natural frequency of DLPFC in 20 Ch-SCZ patients compared to any of 20 healthy subjects (HS). To establish these findings as a reliable neurophysiological biomarker we need to characterize the oscillatory parameters that are defective in patients with early course schizophrenia (EC-SCZ), revealing a core abnormality in the disease that can inform risk. Thus, in Aim 1 we will characterize DLPFC oscillatory activity in EC-SCZ. The presence of prefrontal oscillatory deficits is expected to affect performance in working memory (WM) tasks, which are critically regulated by DLPFC. Aim 2 will assess the association between reduced DLPFC natural frequency and WM performance in EC-SCZ. Overall, the proposed study may provide initial evidence for reduced DLPFC natural frequency as an early biomarker of prefrontal circuit dysfunction in patients with SCZ, which mediates their WM impairments. Future studies involving other psychotic groups and individuals at clinical high risk for psychosis will help establishing if this biomarker is diagnostically specific for SCZ, and if enhances the risk/susceptibility of conversion to psychosis. Furthermore, TMS treatment studies targeting this prefrontal cortical circuit may ameliorate/restore the DLPFC natural frequency and related WM impairments in these patients, thus significantly improving their long-term prognosis.